3-substituted methylene and halomethylene pregnanes



United States Patent 3,365,446 Z a-SUBSTITUTED METHYLENE AND HALO-METHYLENE PREGNANES Alexander D. Cross, Mexico City, Mexico, and ColinC. Beard, Boulder, Colo., assignors to Syntax Corporation, Panama,Panama, a corporation of Panama No Drawing. Continuation-impart ofapplication Ser. No. 530,326, Feb. 28, 1966. This application Feb. 15,1967, Ser. No. 616,209

Claims. (Cl. 260239.55)

ABSTRACT OF THE DISCLOSURE 3fl-hydroxy-, -tetrahydropyr|an-2-yloxy-, and-acyloxypregnanes of the progestational and corticoid series having acyclopropyl or halocyclopropyl group fused to at least one of positionsCl,2 and C-6,7, which are useful for their anabolic, progestational, andcorticoid activity. 3 keto-l,2-methylene-6,7-difluoromethylenepregnaneintermediates and anabolic and progestational agents.

This is a continuation-in-part of Ser. No. 530,326, filed Feb. 28, 1966,now abandoned.

This invention relates to novel cyclopentanophenanthrene derivatives andto their preparation.

This invention is especially directed at novel Sit-tetrahydropyranylethers of the pregnane series of steroids and the corresponding l9-norderivatives thereof having at least one cyclopropyl (methylene) orhalocyclopropyl (halomethylene) group fused to carbons 1 and 2 orcarbons 6 and 7. These steroids 'are represented by the formula:

wherein R is hydrogen, hydroxy, tetrahydropyran-Z-yloxy, or ahydrocarbon carboxylic acid acyloxy group;

R is hydrogen, hydroxy, or a hydrocarbon carboxylic acid acyloxy group;

R is hydrogen, hydroxy, methyl, or when taken together with R the groupin which A is hydrogen or alkyl of up to 8 carbon atoms and B ishydrogen or alkyl or acyl of up to 8 carbon atoms;

R is hydrogen, chloro, or fiuoro;

R is an oxygen atom or the group in which R is hydrogen, hydroXy, orchloro, R and R being the same when R is chloro;

R is hydrogen, methyl, chloro, or fluoro;

R is hydrogen or methyl;

3,365,446 Patented Jan. 23, 1968 Z is a carbon-carbon single bond or amethylene group of the formula x I in which each of X and Y is hydrogen,chloro, or fluoro; and

Z is a carbon-carbon single bond, a carbon-carbon double bond, or amethylene group of the formula in which each of X and Y is hydrogen,chloro, or fluoro, at least one of Z and Z being said methylene group.In the above definitions, the wavy line (i) designates and includes both0: and ,8 configurations.

Rd wherein R is hydrogen or a hydrocarbon carboxylic acid acyl group, Ris hydrogen or methyl, and each of R R R Z and Z is as hereinbeforedefined.

The hydrocarbon carboxylic acyl and acyloxy groups of the presentinvention will contain less than 12 carbon atoms and may be of straight,branched, cyclic or cyclicaliphatic chain structure. These may besaturated, unsaturated or aromatic and optionally substituted byfunctional groups, such as hydroxy, alkoxy containing up to 5 carbonatoms, acyloxy containing up to 12 carbon atoms, nitro, amino,halo-gene, and the like. Typical esters thus include acetate,propionate, enanthate, benzoate, trimethylacetate, t-butylacetate,phenoxyacetate, cyclopentylpropionate, aminoacetate,fi-chloropropionate, adamantoate, and the like.

The compounds of this invention demonstrate corticoid and progestationalactivities. In addition, they possess a high degree of oral activitywhich makes their administration simpler and more easily controlled,resulting in increased application in pharmaceutical compositions. Thispreferred manner of administration also provides the use of a convenientdaily dosage regimen which can be adjusted according to the degree ofafliiction and response to treatment. Most conditions respond well totreatment in the order of magnitude usually employed in the case ofother compounds so used; that is, via a daily dosage unit of from 0.001mg. to 10 mg. per kg. of body weight, the remainder being an inertvehicle or combination thereof. The normally employed pharmaceuticallyacceptable non-toxic compositions are employed in the usual forms.

In particular, those compounds represented by Formula 70 I above inwhich at least one of R and R is other than hydrogen exhibit corticoidactivities thus making them useful as anti-inflammatory agents. Apreferred and especially useful class of these compounds is representedby Formula II:

C HaR wherein each of X and Y is as hereinbefore defined, R is hydroxyor hydrocarbon carboxylic acid acyloxy, R is hydrogen or hydroxy, R ismethyl or when taken together with R isopropylidenedioxy, and R ishydrogen or fiuoro.

Those compounds of Formula I above in which each of R R and R ishydrogen are progestational agents and are useful in the control andregulation of fertility and in the management of various menstrualdisorders. These compounds also are anabolic agents and have varyingdegrees of anti-androgenic, anti-estrogenic, and antigonadotrophicactivities. A preferred class of these compounds is represented byFormula III:

(III) wherein R is hydrogen or methyl and each of R R R", Z and Z is ashereinbefore defined. Of these compounds, those which contain the1,2-methylene group (Z the 6,7-difiuoromethylene group (Z or both the1,2-methylene and 6,7-difiuoromethylene groups are particularly useful.

The novel steroidal ethers of this invention illustrated above areprepared in accordance herewith from the corresponding 3-keto precursorsteroids by reduction of the 3-keto group, such as with lithium aluminumhydride, sodium borohydride, and the like in organic solution followedby etherification of the resultant allylic hydroxyl group withdihydropyran. This etherification reaction is optionally conducted inthe presence of an inert organic solvent, such as benzene, diethylether, and the like, and in the presence of a catalytic amount of anystable sulfonyl chloride, preferably, p-toluenesulfonyl chloride,benzenesulfonyl chloride, methanesulfonyl chloride,p-nitrobenzenesulfonyl chloride, and the like.

The 3fl-acylates hereof are prepared in accordance herewith upontreatment of the 3,8-alcohol (obtained via selective reduction of theketo group) with the appropriate acylating agent conveniently under mildconditions. Useful acylating agents include the corresponding acidanhydrides, such as acetic anhydride and propionic anhydride,Alternatively, the corresponding acylchloride, such as benzoyl chloride,can be employed. The reaction is usually conducted at from roomtemperature to about reflux temperature, generally in the presence ofpyridine as solvent. Typical acyloxy groups thus introduced inaccordance herewith are the hydrocarbon carboxylic acid acyloxy groupslisted and defined hereinbefore.

The 3-keto precursor steroids for the above elaboration are prepared byprocesses described in United States patent application Ser. No.486,226, filed Sept. 9, 1965, and Ser. No. 499,092, filed Oct. 20, 1965.One particularly useful and novel class of precursors are the1,2-methylene- 6,7-difluoromethylene-l7a-acryloxypregn-4-en-3-ones andthe corresponding l7ct-hydroxy and 17a-deshydroxy derivatives thereof,the preparation of which is described in detail hereinafter. Theselatter compounds, in addition to their usefulness as intermediateshereof, also exhibit anabolic and progestational activities.

The methyleneation reaction hereof by which a halomethylene group isadded in at least one of positions C-1,2 and C-6,7 involves treatment ofa conjugated unsaturated steroid with a molar excess of an alkali oralkaline earth metal salt of a haloacetic acid, such asbromochloroacetic acid, dichloroacetic acid, trichloroacetic acid,chlorofluoroacetic acid, difiuorochloroacetic acid.

It is preferable to conduct this reaction after certain labilesubstituents, such as hydroxy groups, have been protected. Thisprotection is preferably accomplished by converting them to esters,tetrahydropyranyl ethers, or ketones which groups readily facilitate theregeneration of the hydroxyl. This preference is not an absolutenecessity, however, for while free hydroxy groups will often becomeinvolved in side reactions under the conditions of the process, they canbe readily regenerated by execution of a mild hydrolysis aftercompletion of the reaction. Compounds possessing the17a,2l-dihydroxy-ZO-keto system may be protected through formation ofthe 17,20; 20,2l-bismethylenedioxy derivative, such as by treatment withformaldehyde in the presence of acid.

The fused methylene group is introduced by reaction of the unsaturatedsteroid with dimethylsulfoxonium methylide base in dimethylsulfoxide.Alternatively, reductive dehalogenation of the halomethylene group,inserted via the methyleneation reaction described above, such as withlithium aluminum hydride affords the fused methylene group in lieuthereof.

The conjugated unsaturated starting steroid may be prepared in a numberof ways. For example, in the introduction of a double bond betweencarbons 1 and 2, the A ring is first reduced with lithium metal inliquid ammonia providing the 3-keto-5a-pregnane(allopregnane). Upontreatment of the al-lopregnane thus obtained with bromine, sodiumacetate, and p-toluenesulfonic acid, the 2-bromo-3-keto-5a-pregnane isobtained which is dehydrobrominated with calcium carbonate indimethylacetamide to alfol'd the A -unsaturated derivative. Thereafter,the corresponding 1,2-halomethylene derivative or, alternatively, the1,2-methylene derivative is prepared as described hereinbefore. Theintroduction of a double bond between carbons 4 and 5 follows by asequence of bromination followed by dehydrobromination as describedabove. The A -diene system is provided by treating thel,2-substituted-3-keto-4-ene with chloranil in the presence of ethylacetate and acetic acid. Thus, for example, the1,2-methylenepregn-4-en-3-ones and 1,2-methylenepregna- 4,6-dien-3-onesof this invention are prepared as well as the 1,2-halomethylenederivatives thereof.

To provide a 6,7-halomethylene or -methylene substituent, a3-keto-4,6-diene system is first generated, such as by treating thecorresponding 3-keto-4-ene with chloranil in the presence of ethylacetate and acetic acid as described above followed by introduction ofthe C6,7 substituent as described above thus giving the 3-keto-4-enecontaining a 6,7-halomethylene or methylene group, i.e., the6,7-halomethylenepregn-4-en-3-ones and 6,7-methylenepregn-4-en-3-ones.

The halomethylene or methylene group may similarly be inserted atposition C-6,7 in a 1,2-substituted-3-keto- 4,6'diene which is providedvia the procedure outlined above. Thus obtained are the1,2;6,7-bis(halomethylene)- pregn-4-en-3-ones and the correspondingmethylene derivatives thereof.

The addition of the methylene and halomethylene groups in accordancewith the procedures set forth herein at either of positions C-1,2 andC6,7 is accomplished with the orientation of the resultant fusedgrouping including both isomeric alpha and beta configurations invariable ratios. The isomeric product mixture in each instance isconveniently and readily subjected to conventional techniques, such aschromatography, fractioned crystallization, and the like, by which thealpha and beta isomers are separated by virtue of their differentphysical properties. Each isomer can thereafter be subjected to furtherelaboration at other parts of the molecule.

In some instances, one particular configurational isomer predominates inthe reaction mixture. Thus, for example, C-1,2 additions of either themethylene or halomethylene group usually favor the alpha isomer. Thepresence of an 11 p-hydroxyl orients the C-6,7 methylene predominantlyto the beta configuration, but does not alter the usual alpha to betaratio in the halomethylene series. Beta addition in the halomethyleneseries is favored by the presence of a 9a-halo substituent.

The substituents represented by R and R' are preferably present in thestarting steroids although the 6-halo groups may be introduced byconverting the 3-keto-4-ene to its enol ether, such as by treatment withethylorthoformate and treating the thus prepared enol ether intermediatewith N-chlorosuccinimide or perchloryl fluoride, respectively, yieldinga 3-keto-4,6-diene containing a 6- chloro or 6-fiuoro group.

The enol ether may also be treated with N-bromosuccinimide and theresultant 6-bromo compound then dehydrobrominated with calcium oxide toyield the 3- keto-4,6-diene. This upon treatment with chromyl chlorideyields the 6,7-chlorohydrin which, when subjected to the action ofhydrogen bromide in acetic acid, affords the 3-keto-6-chloro-4,6-diene.

The substituents represented and defined by R and R may be present inthe starting steroid or they may be subsequently introduced viaconventional procedures. Thus, a llfl-hydroxy compound is dehydrated toyield the 9(11)-ene. This compound is converted to the 95,115- oxidothrough the bromohydrin intermediate. Treatment of the oxido compoundwith hydrogen fluoride or hydrogen chloride then yields the9a-fluoro-l1B-hydroxy or 9achloro-l lfi-hydroxy compounds.Alternatively, the 9(1l)- ene is treated with chlorine to yield the9a,l1B-dichloro derivative.

The substituents represented by R and R are present in the startingsteroid. l6ot,17a-acetals and ketals are prepared through treatment of a16ot,17a-dihydroxy compound with an aldehyde or ketone in the presenceof an acid, such as perchloric acid. The resultant acetal or ketal, forexample, a 16a,l7a-isopropylidenedioxy derivative, may be utilized as afinal compound or as an intermediate, the group being cleaved withregeneration of the diol by the action of hydrofluoric acid.

The l7a,20;20,2l-bismethylenedioxy protecting group which is providedvia treatment with formaldehyde in the presence of hydrochloric acid isremoved by hydrolysis, such as with hydrofluoric acid to restore thedihydroxy keto side chain. The latter is then converted into thecorresponding 2l-tosylate or 2l-mesylate by treatment withp-toluenesulfonyl chloride or methanesulfonyl chloride. The tosylate ormesylate group is replaced by iodine upon treatment with sodium iodidein mixture with acetone and the resulting 2l-iodo compound isdeiodinated by treatment with sodium bisulfite in mixture with aqueousmethanol or by reaction with chromous chloride thus affording steroidscontaining the 17a-hydroxy20-keto-20- methyl system.

The 1702- and 2l-hydroxyl groups may be etherified with dihydropyran inthe presence of p-toluenesulfonic acid or appropriately esterified withan acylating agent, such as acetic anhydride in acetic acid in thepresence of p-toluenesulfonic acid and the like.

This invention may be better understood by reference to the followingexamples which illustrate but not limit the manner by which it can bepracticed.

EXAMPLE 1 Part A A solution of 200 mg. oflulu-methylene-17a-acetoxypregn-4-ene-3,20-dione in 32 ml. of anhydrousisopropanol and 25 mg. of sodium borohydride is stirred at roomtemperature for 15 hours. One-hundred milliliters of water are added andthe resulting suspension extracted several times with ether. The etherphase is dried over sodium sulfate and evaporated to dryness underreduced pressure to yieldla,2a-methylene-l7u-acetoxypregn-4-eu-3{3-01-20- one which may befurther purified by recrystallization from ether.

Two milliliters of dihydropyran are added to a solution of l g. of1ale-methylene-17a-acetoxypregn-4-en-35-01- 20-one in 15 ml. of benzene.About 1 ml. is removed by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days and is then washedwith aqueous sodium carbonate solution and water, dried and evaporated.The residue is chromatographed on neutral alumina, eluting with hexam:to yieldla,Za-methylene-3,B-tetrahydropyran-Z'-yloxyl7a-acetoxypregn-4-en-20-onewhich is recrystallized from pentane.

Similarly, lfl,2[-1 methylene 3/8 tetrahydropyran 2'-yloxy-17a-acetoxypregn-4-en-20-one is prepared fromIdle-methylene-17a-acetoxypregn-4-ene-3,20-dione.

In like manner, the corresponding 17a-hydroxy and l7a-deshydroxycompounds are prepared, the hydroxy by final hydrolysis.

A mixture of l g. of 11!,20t-11l6thYlCD6-170t-aCetOXY-pregn-4-en-3,8-ol-20-one, 4 ml. of pyridine, and 2 ml. of aceticanhydride is allowed to stand at room temperature for 15 hours. Themixture is then poured into ice water and the solid which forms iscollected by filtration, washed with water, and dried to yield1a,2a-methylene-3B,l7adiacetoxypregn-4-en-20-one which may be furtherpurified through recrystallization from acetonezhexane.

A mixture of 2 g. of 10:,2ot-II16'thYl6I16-l7oc-3C6i0XY-pregn-4-en-35-ol-20-one in 8 ml. of pyridine and an equimolar amount ofbenzoyl chloride is heated at steam bath temperatures for thirtyminutes. The mixture is then poured into ice water and the solid whichforms is collected by filtration, washed with water, and dried to yield10:,20: methylene 3,8-benzoyloxy l7a-acetoxypregn 4- en-20-one which isfurther purified through recrystallization from methylenechloride:hexane.

Upon the substitution of the appropriate acylating agent in the aboveprocedures, the corresponding 3,8-prppionate, -valerate, -caproate,-enanthate, and -adamantoate esters are prepared.

Part B The requisite 1,2-methylene starting compounds for the proceduresdescribed under Part A above are prepared as follows.

To a solution of l g. of l7a-hydroxyprogesterone in 75 ml. oftetrahydrofuran and 125 ml. of liquid ammonia is added over a 20-minuteperiod, 0.27 g. of lithium. The mixture is refluxed with stirring for2.5 hours and its color then discharged 'by the careful addition ofethanol. The resulting solution is allowed to stand at room temperatureuntil the ammonia has evaporated and the residue is next shaken with ml.of 1:1 waterzmethylene chloride. The aqueous layer is separated andextracted with methylene chloride and the combined extracts and organiclayer are dried over magnesium sulfate and evaporated. This residue isdissolved in 100 ml. of 5:9 methylene chloride:acetone and titrated with8 N chromic acid, maintaining a temperature of 25 C. Thirteenmilliliters of water are then added with gentle shaking and the aqueousphase is separated and extracted with methylene chloride. The combinedextracts and organic layer are dried over magnesium sulfate andevaporated to dryness to yield a solid. A solution of 6 g. of the solidthus obtained in 120 ml. of pyridine is added to a mixture of 6 g. ofchromic trioxide in 20 ml. of pyridine. The reaction mixture is allowedto stand at room temperature for 15 hours, diluted with ethyl acetate,and filtered through Celite diatomaceous earth. The filtrate is WashedWell with water, dried, and evaporated to dryness to yieldSet-pregnan-17u-ol-3,20-dione which may be further purified byrecrystallization from acetone hexane.

To a solution of 1 g. of Set-pregnan-17a-ol-3,20-dione and 6.6 g. ofp-toluenesulfonic acid in 330 ml. of glacial acetic acid is added, overa 10 minute period, a solution of 1.1 molar equivalent of bromine and2.45 g. of sodium acetate in 110 ml. of glacial acetic acid. Afterstirring for an additional 10 minute period, a solution of 75 g. ofsodium acetate in 150 ml. of glacial acetic acid is added and stirringis then continued at 20 C. for five minutes. The reaction mixture isnext poured into one liter of ice water and the solid which forms iscollected and dissolved in methylene chloride. This solution is washedwith water, dilute sodium bicarbonate solution and water, dried, andevaporated to dryness. The residue is dissolved in 60 ml. ofdimethylformamide and added to a wellstirred suspension of 12.5 g. ofcalcium carbonate in 440 ml. of dimethylacetamide and is heated atreflux. Refluxing is continued for 45 minutes and the mixture is thenfiltered and the filtrate is evaporated to dryness. This residue ischromatographed on acid washed alumina with 3:1 benzenezchloroform toyield 5ot-pregn-1-en-17ot-ol-3,20-dione which may be recrystallized fromcyclohexanezethyl acetate.

A mixture of 1 g. of Sa-pregn-l-en-17o-ol-3,20-dione, 25 ml. of drybenzene, 5 ml. of ethylene glycol, and 50 mg. of p-toluenesulfonic acidmonohydrate is refluxed for 16 hours using a water separator. Thereaction mixture is then washed with aqueous sodium bicarbonate solutionand Water, dried and evaporated to dryness to yield20,20-ethylenedioxy-5ot-pregn-l-en-17a-ol-3-one which is recrystallizedfrom acetone:hexane.

A solution of 0.5 g. of 20,20-ethylenedioxy-5ot-pregn-1- en-17a-ol-3-onein 5 ml. of dimethyl sulfoxide is added to a solution of one equivalentof dimethylsulfoxonium methylide in dimethylsulfoxide, prepared in themanner of Corey et al., J. Am. Chem. Soc. 87, 1353 (1965). The mixtureis stirred under nitrogen and at room temperature for twenty hours andthen at 50 C. for seven hours. Fifty milliliters of water are then addedand the resulting mixture extracted four times with 50 ml. of ethylacetate. The combined extracts are Washed with water and saturatedaqueous sodium chloride solution, dried over sodium sulfate, andevaporated to dryness. This residue is then chromatographed on silica,eluting with ether: methylene chloride to yield1a,2u-methylene-20,20-ethylenedioXy-Sa-pregnan-17u-ol-3-one and itscorresponding 15,213-methylene isomer.

The 6,7-methylene derivatives are analogously prepared from thecorresponding A starting compounds.

A mixture of 0.5 g. of 1(1,2a-methylene-20,20-ethy1-enediOXy-Sa-pregnan-l7a-ol-3-one in 30 ml. of acetone and 50 mg. ofp-toluenesulfonic acid is allowed to stand at room temperature for 15hours. It is then poured into ice water and extracted with ethylacetate. These extracts are washed with water to neutrality, dried oversodium sulfate, and evaporated to dryness. The residue is trituratedwith ether to yield 1aim-methylene-Sa-pregnan-17aol-3,20-dione which isrecrystallized from acetonezhexane.

To a stirred solution of 1 g. ofIaJa-methylene-Saplegnan-17OL-Oi-3,20-dl0116 in 17 ml. of chloroform and20 ml. of glacial acetic acid, cooled to C., are added a few drops of asolution of hydrogen bromide in acetic acid followed by a solution of0.46 g. of bromine in 12 ml. of chloroform, the latter at such a ratethat the reaction mixture maintains a pale yellow color. A cold solutionof 2.5 g. of sodium acetate in 17 ml. of water is then added. The layersare separated and the aqueous layer is extracted with chloroform. Thecombined extracts and organic layer are washed with water, dilutepotassium bicarbonate solution, and again with water, dried over sodiumsulfate, and evaporated to dryness to yield the 4- bromo intermediate, 1g. of which is dissolved in 20 ml. of dimethylformamide containing 0.5g. of lithium chloride. This solution is stirred under nitrogen at steambath temperatures for four hours. After cooling to 10 C., 11 ml. ofwater are added with stirring at such a rate that the temperature ismaintained below 30 C. Stirring in an ice bath is continued until solidforms and this material is then collected by filtration, washed withcold 1:1 Water: dimethylformamide and then water, and dried to yield101.204 methylenepregn 4-en-17ot-ol-3,20-dione which is further purifiedthrough recrystallization from acetone with charcoal decolorization asnecessary.

A mixture of 1 g. of 1a,2et-methyleneprcgn-4-en-17aol-3,20-dione, 1 g.of p-toluenesulfonic acid monohydrate, 50 ml. of acetate acid, and 25ml. of acetic anhydride is allowed to stand at room temperature for 24hours and then poured into water and stirred. This mixture is thenextracted with methylene chloride and these extracts are dried andevaporated to yield 1et,2m-methylene-17aacetoxy-pregn-4-ene-3,20-dionewhich is recrystallized from acetonezether.

Analogously,1t3,Zfl-methylene-ZO,20-ethylenedioxy-5apregnan-17a-ol-3-one is treatedas set forth in the preceding three paragraphs to afford 16,2B-methylene-17aacetoxypregn-4-ene-3,20-dione. Alternatively, theisomeric product mixture can be so treated and the resultant productmixture separated at reaction end into the respective isomers.

A double bond may be inserted between carbons 6 and 7 as follows.

A mixture of 1 g. of 1,Z-methylene-l7a-acetoxypregn- 4-ene3,20-dione, 2g. of chloranil, 15 ml. of ethyl acetate, and 5 ml. of acetic acid isrefluxed under nitrogen for 96 hours. The mixture is then cooled andwashed with cold 10% aqueous sodium hydroxide until the washings arecolorless. The organic solution is dried over sodium sulfate and theethyl acetate removed by evaporation. Upon chromatography of the residueon neutral alumina there is obtained1,2-methy1ene-l7a-acetoxypregna-4,6-diene- 3,20-dione which may befurther purified by recrystallization from acetone:hexane.

The M -diene may then be treated as described in Part A above to yield1u,2a-methylene-3fi-tetrahydroypran-T- yloxy 17a acetoxypregna4,6-dien-20-one and 1,3,26- methylene 3B tetrahydropyran 2 yloxy17a-acetoxypregna-4,6-dien-20-one.

In a similar manner, the C6,7 double bond can be introduced as describedabove into 1,2-methylenepregn-4- ene-3,20-dione,1,2-methylene-6u-chloropregn-4-ene-3,20- dione, and 1,2 methylene 6o:chloro 17x-acetoxypregn-4-ene-3,20-dione (respectively preparedaccording to the procedures illustrated in Part B above fromprogesterone, 6a-chloroprogestcrone, and 6oc-Ch1Ol'O-17oL-hY-droxyprogesterone with the acylation step omitted for the first twocompounds) to give 1,2-methylenepregna-4,6- diene 3,20 dione, 1,2methylene-6-chloropregna-4,6- diene 3,20 dione, and 1,2 methylene 6chloro-17aacetoxypregna 4,6 diene-3,20-dione, respectively. Thesecompounds are reduced and etherified by the procedure of Part A above torespectively yield 1,2-methylene-3fltetrahydropyran 2 yloxypregna4,6-dien-20-one, 1,2- methylene 3B tetrahydropyran 2 yloxy6-chloropregna 4,6 diene 20 one, and l,2-methylene-3fltetrahydropyran 2yloxy 6 chloro 17a-acetoxypregna-4,6-dien-20-one. Likewise, the othermethylene pregnanes of this invention, including the l7tx-deshydroxy and16a-methyl derivatives, are prepared.

9 EXAMPLE 2 Part A By following the reduction and etherificationprocedure outlined in Part A of Example 1,3,6-tetrahydropyran-2'-yloxy-6a,7ot-difluoromethylene-17a acetoxypregn-4-ene-20-one and 65,75 difluoromethylene-17a-acetoxypregn-4-en-20-oneare prepared from 6a,7a-difluoromethylene-17a-acetoxypregn-4-ene 3,20dione and 65,7B-difiuoromethylene-l7u-acetoxypregn-4-ene-3,ZO-dione.

Base hydrolysis affords the free alcohols thusly:

A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5ml. of methanol is added over thirty minutes to a refluxing solution of.1 g. of 3fi-tetrahydropyran-Z-yloxy-6,7-difluorornethylene-17aacetoxypregn- 4-ene20-one in 30 ml. of methanol under nitrogen. Thesolution is refluxed for two hours, cooled, neutralized with aceticacid, and concentrated under reduced pressure. After the addition ofwater, the solid which forms is collected by filtration and dried toyield 3/8-tetrahydropyran-2'-yloxy-6,7-difluoromethylenepregnl-en-l7a-ol20- one which is recrystallized from acetone:hexane.

The corresponding 3,8-acylates are prepared upon treatment of thereduced Bfl-alcohol according to the procedures set forth in the lastthree paragraphs of Part A of Example 1.

The above procedures are likewise useful in the 1704- deshydroxy series.

PartB The requisite 6,7-difluoromethylene starting compounds for Part Ahereof are provided as follows.

To a stirred and refluxing solution of 1 g. of 170C-acetoxypregna-4,6-diene-3,20-dione in 8 ml. of dimethyl diethyleneglycolether is added in a dropwise fashion over a two hour period, a solutionof thirty equivalents of sodium chlorodiiluoroacetate in 30 ml. ofdimethyl diethyleneglycol ether. At the end of the reaction period,which may be followed by the UV. spectra, the mixture is filtered andevaporated in vacuo to dryness. The residue is added to methanolicpotassium hydroxide and this mixture is heated briefly at reflux andpoured into ice water. The solid which forms is collected, washed withwater, dried, and chromatographed on alumina, eluting with methylenechloride to yield6a,7a-difluoromethylene-l7a-acetoxypregn-4-ene-3,ZO-dione and itscorresponding 6B,7fi-difluoromethylene isomer.

In a similar manner, 6-chloro-17u-acetoxypregn-4,6- dime-3,20 dione istreated as described in Part B above to give 6;?chloro6,7-difluoromethylene 17a acetoxypregn-4-ene-3,20 dione which isreduced and etherified as described in Part A of this example to yield3fi-tetrahydropyran-2-yloxy-6fi-chloro-6,7-difluoromethylene170cacetoxypregn-4-en-20 -one.

By substituting sodium trichloroacetate in lieu of sodiumchlorodifiuoroacetate in practicing the foregoing procedure, there isobtained the corresponding dichloromethylene steroids. Likewise, the useof sodium chlorofluoroacetate and sodium dichloroacetate thereinproduces the monofluoroand monochloromethylene derivatives,respectively.

The other 6,7-difiuoromethylene pregnanes of this invention, includingthe 17a-deshydroxy derivatives, are also thus prepared, the isomersbeing separable by chromatography.

Analogously, the foregoing procedures are used to prepare thecorresponding 1,2-difiuorornethylene pregnanes of this invention.

EXAMPLE 3 Part A lale-methylene-6a,7ot-difluoromethylene 17aacetoxypregn-4-ene-3,ZO-dione is reduced and etherified as outlined inPart A of Example 1 yielding lulu-methylene-3fl-tetrahydropyran-2'-yloxy6a,7a difluoromethylene-l7a-acetoxypregn 4-ene-20-one.

In a similar manner, the corresponding C-l,2 and C6,7 beta isomers areso prepared.

The procedures set forth in the last three paragraphs of Part A ofExample I prepare the corresponding 3fi-acylates from the precursor3B-alcohols.

The foregoing are likewise useful in the l7a-deshydroxy series.

Base hydrolysis according to the third paragraph of Part A of Example 2gives the corresponding 17a-hydroxy compounds.

Part B The requisite starting compounds above are provided by treating1,2 -methylene-17a-acetoxypregna-4,6-diene- 3,20-dione (prepared asdescribed in Part B of Example 1) with sodium chlorodifiuoroacetate asoutlined in the second paragraph of Part B of Example. 2 to yield 1,2-methylene-6,7-difluoromethylene 17cc acetoxypregn-4- ene-3,20-dione.

In a similar manner as that described in this example earlier,1,2-methylene 3 8 tetrahydropyran-2-yloxy-6/3-chloro-6,7-difluoromethylene 17a acetoxypregn-4-en- 20-one is preparedfrom 1,2-rnethylene-6-chloro-17a-acetoxypregn-4,6-diene-3,20-dione.Similarly prepared are the other 1,2-methylene-6,7-difluoromethylenepregnanes of this invention, the isomers being separable, in eachinstance, via conventional procedures, such as preparativechromatography.

EXAMPLE 4 Part A 1a,2ot methylene-2l-acetoxypregn 4ene-11fi,17otdiol-3,20-dione is selectively reduced and then treatedwith dihydropyran as described in Part A of Example 1 to yield1ale-methylene-3fl-tetrahydropyran-2'-yloxy-2lacetoxypregnl-ene-ll;3,l7a-diol-20-onewhich may be treated with base to give the corresponding 21-01 asfollows.

A suspension of 1 g. of 1u,Zea-methylene-3/8-tetrahydropyran-2-yloxy-2 l-acetoxypregn-4-ene-1 1B, 1 70t-di01-20-OI16 in 60 ml. of. methanol istreated with a solution of 1 g. of potassium carbonate in 6 ml. ofwater. The mixture is heated at 0 C. for one hour, cooled in ice, anddiluted with water. The solid which forms'is collected by filtration,washed with water, and dried to yieldlulu-methylene-3,B-tetrahydropyran-2'-yloxypregn-4-ene-1 1/3, 1 711,2 1-triol-20-orie which is recrystallized from acetonezhexane.

In an analogous manner, the corresponding 15,25- methylene-33-tetrahydropyran 2 yloxypregn-4-ene-l1fi, 17a,21-triol-20-one is thusprepared.

The corresponding SB-ac'ylates are prepared according to the proceduresgiven in the last three paragraphs of Example 1 (Part A).

The foregoing are likewise useful in the l7a-deshydroxy series.

Part B pregn-4-ene-11 3,17a,21-triol-3,20-dione as follows.

To a solution of 5 g. of pregn-4-ene-l1fi,l7oc,21-triol- 3,20-dione in200 ml. of chlorform are added 40 ml. of 37% aqueous formaldehyde and 5ml. of concentrated hydrochloric acid. The mixture is stirred for 48hours at room temperature and the two layers then separated. The aqueouslayer is extracted with chloroform and the combined organic layer andchloroform extracts are washed with water to neutrality, dried oversodium sulfate, and evaporated to dryness to yield17a,20;20,21-bismethylenedioxypregn-4-en-l1,8-01-3-one which isrecrystallized from methanolzether.

The product thus formed is treated according to the procedures of Part Bof Example 1 to consecutively form the corresponding Sa-allOpregnane, Aderivative, and

1 1 finally, 1,2 methylene-17a,20;20,21bismethylenedioxypregn-4-en-l1l3-ol-3-one.

A suspension of 1 g. of 1,2-rnethylene-17a,20;20,21-bismethylenedioxypregn-4-en-11fi-ol-3-one in 10 ml. of 48% aqueoushydrofluoric acid is stirred at C. for 90 minutes. At the end of thistime, the reaction mixture is neutralized with aqueous potassiumbicarbonate solution and extracted with ethyl acetate. These extractsare evaporated to dryness under reduced pressure and chromatographed onsilica gel with 2:1 hexanezethyl acetate to yield1,2-methylenepregn-4-ene-l1B,17a,21-triol- 3,20-dione which may befurther purified through recrystallization from isopropanol.

A mixture of 1 g. of 1,2-methylenepregn-4-ene-11fi,17oc,21-triol-3,20-dione, 4 ml. of pyridine, and 2 ml. of acetic anhydride isallowed to stand at room temperature for fifteen hours. The mixture isthen poured into ice water, and dried to yield1,2-methylene-21-acetoxypregn-4-ene- 11B,l 7o;-diol-3,20-dione which maybe further purified through recrystallization from acetonezhexane.

By following the procedure outlined in Example 1, Part B, for insertinga double bond at C-6,7 on either of the compounds prepared immediatelyabove, 1a,2amethylene-2l-acetoxypregna 4,6-diene-11,8,17a-diol-3,20-dione and 1fi,2fi-methylene-21-acetoxypregna-4,6 diene-11fl,17a-diol-3,20-dione are prepared which are similarly treated as inPart A hereof to give the corresponding 3fi-tetrahydropyran-2'-yloxy-A-dienes.

In a similar manner, 9a,1lfl-dichloropregn-4-ene-17a, 21-diol-3,20-dioneis used as a starting steroid in Part B hereof except for the procedureset forth in the immediately preceding paragraph to afford1,2-methylene- 90:,1 1 /3-dichloro-21-acetoxypregn 4en-17a-o1-3,20-dione which is treated as in Part A hereof thus giving1a,2otrnethylene-3fi-tetrahydropyran-2-yloxy9a,11[3-dichloropregn-4ene-17a,21-diol-20-one and the corresponding 15,Zfi-methylene isomer thereof. 9e-11/3-dichloropregn-4- ene-3,20-dione issimilarly treated, including the C6,7 double bond insertion procedure inPart B hereof, but omitting the bismethylenedioxy protecting groupprocedures to give 1,2-methylene-3fi-tetrahydropyran-T- yloxy-901,113-clichloropregna-4,6-dien-2O-one. The other 1,2-methylene corticoids ofthis invention, such as the corresponding corticoids containing a16u-methyl, 90- fiuoro, and combinations thereof, are similarlyprepared, the isomers, in each instance, being separable bychromatography as set forth above.

In the 6,7-methylene series in conjunction with an 11;?- hydroxy group,the beta isomer predominates.

EXAMPLE 5 Part A Reduction and etherification of6oz,7rx-dif1uoromethylene-21-acetoxypregn-4-en-1 113,17a-dio1-3,20-dione with subsequent basic hydrolysis as described inPart A of Example 4 affords3[i-tetrahydropyran-2'-y1oxy-6a,7adifiuoromethylenepregn-4-ene-11fi,17a,21-triol-20-one.

Similarly, 3 ,B-tetrahydropyran-2-yloxy-66,75difluoromethylenepregn-4-ene-11fi,17a,21 triol one is thus prepared fromthe corresponding C6 8,7,B starting compound.

Treatment of the 3fi,11 3,17a,21-tetrol with dihydropyran affords the3,6,21-bistetrahydropyran-2-yloxy ether thereof.

The procedures of the last three paragraphs of Part A of Example 1prepare the corresponding 3,8-acylates of the free alcohols after priorprotection of the side chain.

The foregoing are likewise useful in the 17a-deshydroxy series.

Part B The requisite starting steroids for the above procedure isprepared by inserting a double bond at (1-6.7 in 170;, 20;20,2lbismethylenedioxypregn 4 en 11fl-ol-3-one (prepared by the procedureprovided in Example 4) following the procedure set forth therefor inExample 1, Part B, followed by treatment of the thus prepared 4,6- dienewith sodium chlorodifiuoroacetate as given in Exis prepared by insertinga double bond at C-6,7 in 17a,20,20,21-bismethylenedioxypregn-4-en-11B-ol-3-one isomers separable bychromatography. Finally, the protecting group is removed and the21-acetoxy group is provided by the procedures given in Part B, Example4.

Likewise, by practicing the procedures outlined in Parts A and B of thisexample on 16u-methylpregn-4-ene-11p, 17a,21-triol-3,20-di0ne,9ot-fiuoro-16a-methylpregn-4-ene- 113,17a,21-triol-3,20-dione, and6a,16a-dimethy1pregn-4- ene-l1fl,17u,21-triol-3,20-dione, there areultimately respectively obtained3fi-tetrahydropyran-2-yloxy-6,7-difluoromethylene-16a-methylpregn-4-ene-1118,17a,21triol- 20-one;3B-tetrahydropyran-2-yloxy-6,7-difluoromethylene-9ot-fluoro-lGa-methylpregn4 ene-1l/3,17a,21-triol- 3,20-dione; and3,8-tetrahydropyran-2-yloxy-6,7-difluoromethylene-6a,16a dimethylpregn 4ene 11B,l7 x,21- triol-3,20-dione. Similarly, the other6,7-difluoromethy1- ene corticoids of this invention, including the11p,17-diols and the 17a-dehydroxy compounds are prepared. Byeliminating the hydrolysis step of Part A hereof, the corresponding21-acetates are prepared. In the case of 9afluoro-16oa methylpregn-4-ene11fl,17a,21 triol-3,20- dione mentioned above, as well as the other9a-i'luoro compounds contemplated herein, the 65,7/3-difiuoromethyleneisomer is favored.

EXAMPLE 6 Part A In the same manner as described in Part A of Example 1,6a,7a-difluoromethylene-l6a,17a-isopropylidenedioxy-2l-acetoxypregn-4-en-115-ol-3,20-dione is converted to3,6-tetrahydropyran-2 y1oxy-6a,7a difluoromethylene-16a,17a-isopropylidenedioxy-21 acetoxypregn-4-en-l 1/3- ol-20-one. The2l-acetoxy group is thereafter removed with base as given in Example 4(Part A) to give 3B-tetrahydropyran-Z yloxy-6m,7udifluoromethylene-16a,17aisopropylidenedioxypregn-4-ene-1113,21-diol-20-one.

Likewise, the corresponding 65,76-difiuoromethylene isomer is formedfrom the requisite C-6,6,7/3 starting compound.

The corresponding 3 fi-acylates are prepared via the procedures of thelast three paragraphs of Example 1 (Part A).

The foregoing are likewise useful in the 17a-dCS- hydroxy series.

Part B The requisite starting compounds for the procedure illustratedabove is provided by procedures analogous to those described in Part Bof Example 5 from 1611,17aisopropylidenedioxypregn-4-ene 11,6,21di0l-3,20-dione omitting the procedures for the introduction and removalof the bismethylenedioxy protecting group.

In a similar manner to that outlined above, fie-tetrahydropyran-Z-yloxy6,7 difiuoromethylene-9rat-fluoro-16a,17a-isopropylidenedioxypregn-4-ene-115,21 di0l-20- one and3fi-tetrahydropyran-2-yloxy-6,7-difluoromethylene-6fl,9ot-difiuoro16a,17a isopropylidenedioxypregn- 4-ene-11/5,21-diol-20-one are preparedfrom the corresponding starting steroids, the C-6/3,75 isomerpredominating in each instance. By omitting the last procedure mentionedin Part A above, the corresponding 21- acetoxy compounds are provided.

By following the procedure outlined in Example 4 for inserting the1,2-methylene and 3fi-tetrahydropyran-2'- yloxy groups but omitting thestep for the insertion and removal of the bismethylenedioxy protectinggroup on 6dfluoro 16a,17o isopropylidenedioxypregn-4-ene-11 19,21-dio1-3,20-dione and 6 x,9oc-difill0l016a,17u-isopropylidenedioxypregn-4-ene-11B,21-di0l-3,20-dione, there arerespectively obtained, 1,2-n1ethylene-3B-tetrahydropyran-2-yloxy-6u-fiuoro 16a,17a-isopropylidenedioxypregn-4- 13ene-11fl,21-diol-20-one and 1,2-methylene-3 8-tetrahydropyran-2-yloxy6a,9adifluoro-16a,17x-isopropylidenedioxypregn-4-ene-11,8,21-dibl-20-one.Similarly, by eliminating the last step thereof, the corresponding21-acetoxy derivatives are obtained.

EXAMPLE 7 Part A By practicing the procedures set forth in Part A ofExample 4 on1,2-methylene-6,7-difluoromethylene-2lacetoxypregn-4-ene-11fl,17a-diol-3,20-dione,there is obtained1,Z-rnethylene-3,6-tetrahydropyran-2'-yloxy-6-,7-difluoromethylenepregn-4-ene-1 1,8, 170:,21-IIiOl-20-OI16.

The corresponding 3,3-acylates are prepared via the procedures of thelast three paragraphs of Example 1 (Part A).

The foregoing are likewise useful in the l7oc-deS- hydroxy series.

PartB Upon subjecting 17u,20;20,21-bismethylenedioxypregna-4,6-dien-11,6-ol-3-one (prepared as described inthe first paragraph of Part B of Example 5) to the procedure set forthin Example 1 for the insertion of a methylene group,65,7;3-methylene-17u,20;20,2l-bismethylenedioxypregn-4-en-11fi-ol-3 onetogether with some of the corresponding C6a,7 a-methylene isomer isprepared. Thereafter, hydrolysis ofthe side chain protecting group bythe procedure given in Example 4 (Part B) and Selective reduction andetherification at C-3;provid'es 3B- tetrahydropyran-2'-yloxy 66,7 8methylenepregn-4-ene- 11,6,17a,21-trio1-20-0ne. The alpha isomer issimilarly elaborated.

The corresponding 3/3-acylates are prepared via the procedures of thelast three paragraphs of Example 1 (Part A). i 4

The foregoing are likewise useful inthe 17ix-deshydroxy series. I

What is claimed is: y

1. Steroids of the formula:

wherein R is hydrogen, hydroxy, tetrahydropyran-Z-yloxy, or ahydrocarbon carboxylic acid acyloxy group of less than 12 carbon atoms;

R is hydrogen, hydroxy, or a hydrocarbon carboxylic acid acyloxy groupof less than 12 carbon atoms;

R is hydrogen, hydroxy, methyl, or when together with R the group inwhich A is hydrogen or alkyl of up to 8 carbon atoms and B is hydrogenor alkyl or acyl of up to 8 carbon atoms; R is hydrogen, chloro, orfluoro; R is an oxygen atom or the group I .H in which R is hydrogen,hydroxy, or chloro, R and R being the same when R is chloro; R ishydrogen, methyl, chloro, or fluoro; R is hydrogen or methyl; Z is acarbon-carbon single bond or a methylene group of the formula x Y inwhich each of X and Y is hydrogen, chloro, or fluoro; and Z is acarbon-carbon single bond, a carbon-carbon double bond, or a methylenegroup of the formula X 1 in which each of X and Y is hydrogen, chloro,or fiuoro, at least one of Z and Z being said methylene group. 7 v v v I2. Steroids of claim 1 wherein R is hydroxy or a hydrocarbon carboxylicacid acyloxy group of less than 12 carbon atoms;

R is hydrogen or hydroxy; R is a-methyl or when taken together with Rthe group R is hydrogen or fluoro; R is the group ..'.H in which R ishydroxy; R is hydrogen; R is methyl; Z is a carbon-carbon single bond;and Z is the group CXY ,H in which each of X and Y is hydrogen orfluoro. 3. Steroids of claim 2 wherein each of R and R is hydroxy and Ris a-methyl.

4. Steroids of claim 2 wherein R is hydroxy, R is hydrogen, and R isa-methyl.

5. Steroids in claim 1 wherein R is hydrogen; R is hydrogen, hydroxy, ora hydrocarbon carboxylic acid acyloxy group of less than 12 carbonatoms; R is hydrogen or a-methyl; R is hydrogen; R is the group ...H inwhich R is hydrogen; R is hydrogen, chloro, fiuoro, or methyl; R ishydrogen or methyl;

Z is the group :CHz; and

Z is a carbon-carbon single bond or a carbon-carbon double bond.

6. Steroids of claim wherein R is hydrogen, R is chloro, R is methyl,and Z is a carbon-carbon double bond.

7. A steroid of claim 5 wherein R is hydrogen, R is tit-methyl, R ischloro, R is methyl, and Z is a carboncarbon single bond.

8. A steroid of claim 5 wherein R is hydrogen, R is ot-methyl, each of Rand R is methyl, and Z is a carbon-carbon single bond.

9. Steroids of claim 1 wherein R is hydrogen;

R is hydrogen, hydroxy, or a hydrocarbon carboxylic acid acyloxy groupof less than 12 carbon atoms;

R is hydrogen or a-methyl;

R is hydrogen;

R is the group in which R is hydrogen;

R is hydrogen, chloro, fiuoro, or methyl;

R is hydrogen or methyl;

Z is a carbon-carbon single bond; and

Z is the group 10. Steroids of claim 9 wherein each of R and R ishydrogen.

11. Steroids of claim 9 wherein R is hydrogen and R is chloro.

12. Steroids of claim 9 wherein R is acetoxy and R is hydrogen.

13. Steroids of claim 9 wherein R is acetoxy and R is chloro.

14. Steroids of the formula:

wherein R is hydrogen or a hydrocarbon carboxylic acid acyl group ofless than 12 carbon atoms;

R is hydrogen, hydroxy, or a hydrocarbon carboxylic acid acyloxy groupof less than 12 carbon atoms;

16 R is hydrogen or methyl; R is hydrogen, chloro, fluoro, or methyl; Ris hydrogen or methyl; Z is a carbon-carbon single bond or a methylenegroup of the formula torn; and

Z is a carbon-carbon single bond, a carbon-carbon double bond, or amethylene group of the formula at least one of Z and Z being saidmethylene group. 15. Steroids of claim 14 wherein Z is the group Zorn16. Steroids of claim 14 wherein Z is a carbon-carbon single bond and Zis the group wherein R is hydrogen, hydroxy, or a hydrocarbon carboxylicacid acyloxy group of less than 12 carbon atoms.

References Cited UNITED STATES PATENTS 3,127,396 3/1964 Waichert et al.260239.5 3,243,434 3/1966 Krakower 260-23955 LEWIS GOTTS, PrimaryExaminer. H. FRENCH, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,365,446 January 23, 1968 Alexander D. Cross et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 4, line 6, for "acryloxypregn" read acyloxypregn column 12, lines3 to 4, for "Exis prepared by inserting a double bond at C-6,7 in" readExample 2, Part B, giving line 22, for "dehydroxy" read the6,7-difluoromethylenedeshydroxy column 14, lines 20 to 24, the formulashould appear as shown below instead of as in the patent:

Signed and sealed this 25th day of March 1969.

(SEAL) Attest EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting OfficerCommissioner of Patents

